Positron emission tomography (PET) plays a vital role in the diagnosis of health and disease. Over the last half decade, steady advancements in PET instrumentation and synthetic chemistry have required substantial quantities of the cyclotron produced positron emitting isotopes, 11C, 13N, 15O, and 18F. Carbon, nitrogen and oxygen offer the advantage of seamless integration into existing compounds without altering their chemical properties. 18F labeled compounds, as analog species, mimic many natural substances but fail to completely navigate most biochemical pathways. However, the favorable half-life of 18F (t1/2=109 min) proves to be well suited for most time scales explored in the body.
The value of PET, well represented by the wide use of [18F]-fluorodeoxyglucose ([18F]-FDG) in the clinical environment, bridges cardiology, oncology and the neurosciences. Within the last decade, a significant percentage of new PET installations have occurred at oncology sites for the diagnosis and staging of disease as well as monitoring the progression of treatment regimens. Another major consumer of fluorinated agents, including [18F]-FDG, has developed within the pharmaceutical companies. Coinciding with the arrival of commercial small animal scanners, monitoring drug behavior on the tracer level in vivo has proven more effective than observing indirect responses in large patient demographics.
A natural outcome of the increasing clinical [18F]-FDG studies in the late 1990s was the birth of commercial PET isotope distribution centers. CTI installed the first commercial purpose cyclotron in 1990 which has proliferated to nearly 150+11 MeV RDS proton (only) cyclotrons nationwide. These distribution centers operate with a capacity that has changed the architecture of medical imaging centers. The formation of satellite imaging facilities is now realized as long as a host cyclotron falls within a driving radius on the order of the labeled half-life. However, geography has limited these sites to providing only 18F, as the positron emitting isotopes of oxygen, nitrogen, and carbon have short half-lives that do not lend themselves to transport over long distances (>few kilometers).
The freedom to label authentic ligands, native to the body's physiological environment, forces the expansion of PET beyond the pure positron emitters stressing development of production systems for non-conventional PET isotopes. Much of the growing need for these non-conventional isotopes focuses on the long-lived neutron deficit radiohalogens, specifically 124I (t1/2=4.17d, Eβ+=2.13 MeV, Iβ+=22%, γ=603 keV). The incorporation of radiohalogens into organic molecules is supported by a vast body of literature recently reviewed (Bolton. J. Label. Compd. Radiopharm., 45, 485 (2002); Adam et al., Chem. Soc. Rev., 34, 153 (2004)). The promising clinical aspects of 124I have led to investments among several research institutions and commercial companies to produce multi-mullicurie quantities for distribution purposes. The combination of physiological versatility and well-known labeling chemistry ensures a pivotal role for 124I in developing molecular agents of diagnostic and therapeutic value.
Traditionally, the bulk output of radiohalogens, including 124I, comes from a few centers with large multi-particle cyclotrons (i.e. 30 MeV protons, 15 MeV deuterons) driving the 124Te(d, 2n)124I reaction (Sharma et al., J. Lab. Compd. Radiopharm., 2, 17 (1969); Lambrecht et al., J. Radioanal. Nucl. Chem. Letters, 127, 143 (1988); and Firouzbakht et al., Nicl. Insrtum. Meth. Phys. Research, B79, 909 (1993)). However, a large population of low energy biomedical cyclotrons have benefited from the moderate yields of the 124Te(p,n)124I pathway (Scholten et al., Appl. Radiat. Isot., 46, 255 (1995)). The high radionuclidic purity and modest contributions from the secondary 124Te(p,2n)123I reaction present attractive aspects for targetry development along this path. Thus, the large commercial presence of these biomedical cyclotrons, distributed across the United States (i.e. 11 MeV CTI RDS; 16 MeV GE PETtrace), normally supplying curie quantities of [18F]-FDG, provide an appropriate base for a steady source of 124I. Unfortunately, efforts to produce this radiohalogen have generally gone undeveloped. A combination of factors have prevented expansion, centering primarily on the complexity of the target systems, expense of the enriched substrates, low reaction yields, and extensive post-processing to reclaim the target material.
It is known that elemental tellurium does not possess the necessary thermal and physical properties for a stable solid matrix needed in the harsh irradiation conditions of a cyclotron target. In addition, separation of the 124I product from the packed target powder requires wet chemistry techniques, making post-processing arduous. Pairing tellurium with a low-Z element, forming a binary compound, significantly improves the thermal performance and physical nature of target material. The preferred method involves the irradiation of binary compounds, specifically tellurium dioxide (TeO2) and copper telluride (Cu2Te). The bombardment of glassy tellurium dioxide melts has prevailed as the material of choice given its high mass fraction and commercial availability. The added benefit of dry distillation to recover the 124I product proves more favorable for TeO2 as each thermal cycle leaves the target in a preparative state for the next irradiation.
Development of a reliable methodology to produce 124I on low energy cyclotrons is largely discouraged in the literature but sufficient amounts have been demonstrated on 13 MeV machines using conventional targets (McCarthy et al., Proceedings of the 8th Workshop on Targetry and Target Chemistry, St. Louis, Mo., 127 (1999); Sheh et al., Radiochem. Acta, 88, 169 (2000); and Qaim et al., Appl. Radiat. Isot., 58, 69 (2003). Using the existing systems and targets, obtaining useful quantities of 124I via the (p,n) reaction at proton energies below 13 MeV becomes difficult as the saturation yield drops by nearly a factor of three from an incident energy of 13 to 11 MeV. In addition, commitment to the required startup costs overwhelms most PET sites interested in 124I research. Thus, a need exists for an improved system and target material for the production of 124I utilizing low energy biomedical cyclotrons.